TY - JOUR
T1 - Neurotensin differentially regulates bile acid metabolism and intestinal FXR-bile acid transporter axis in response to nutrient abundance
AU - Li, Jing
AU - Song, Jun
AU - Yan, Baoxiang
AU - Weiss, Heidi L.
AU - Weiss, L. Todd
AU - Gao, Tianyan
AU - Evers, B. Mark
N1 - Publisher Copyright:
© 2021 Federation of American Societies for Experimental Biology
PY - 2021/5
Y1 - 2021/5
N2 - Studies demonstrate a role for neurotensin (NT) in obesity and related comorbidities. Bile acid (BA) homeostasis alterations are associated with obesity. We determined the effect of NT on BA metabolism in obese and non-obese conditions. Plasma and fecal BA profiles were analyzed by LC-MS/MS in male and female NT+/+ and NT−/− mice fed low-fat (LFD) or high-fat diet (HFD) for 6 weeks (early stage of obesity) or greater than 20 weeks (late stage of obesity). The nuclear farnesoid X receptor (FXR) and BA transporter mRNA expression were assessed in ileum, mouse enteroids, and human cell lines. HFD decreased plasma primary and secondary BAs in NT+/+ mice; HFD-induced decrease of plasma BAs was improved in NT-deficient mice. In NT+/+ mice, HFD inhibited ileal FXR and BA transporter expression; HFD-decreased expression of FXR and BA transporters was prevented in NT−/− mice. Compared with LFD-fed NT+/+ mice, LFD-fed NT−/− mice had relatively lower levels of ileal FXR and BA transporter expression. Moreover, NT stimulates the expression of FXR and BA transporters in Caco-2 cells; however, stimulated expression of BA transporters was attenuated in NT−/− enteroids. Therefore, we demonstrate that HFD disrupts the BA metabolism and ileal FXR and BA transporter axis which are improved in the absence of NT, suggesting that NT contributes to HFD-induced disruption of BA metabolism and plays an inhibitory role in the regulation of ileal FXR and BA transporter signaling under obese conditions. Conversely, NT positively regulates the expression of ileal FXR and BA transporters under non-obese conditions. Therefore, NT plays a dual role in obese and non-obese conditions, suggesting possible therapeutic strategies for obesity control.
AB - Studies demonstrate a role for neurotensin (NT) in obesity and related comorbidities. Bile acid (BA) homeostasis alterations are associated with obesity. We determined the effect of NT on BA metabolism in obese and non-obese conditions. Plasma and fecal BA profiles were analyzed by LC-MS/MS in male and female NT+/+ and NT−/− mice fed low-fat (LFD) or high-fat diet (HFD) for 6 weeks (early stage of obesity) or greater than 20 weeks (late stage of obesity). The nuclear farnesoid X receptor (FXR) and BA transporter mRNA expression were assessed in ileum, mouse enteroids, and human cell lines. HFD decreased plasma primary and secondary BAs in NT+/+ mice; HFD-induced decrease of plasma BAs was improved in NT-deficient mice. In NT+/+ mice, HFD inhibited ileal FXR and BA transporter expression; HFD-decreased expression of FXR and BA transporters was prevented in NT−/− mice. Compared with LFD-fed NT+/+ mice, LFD-fed NT−/− mice had relatively lower levels of ileal FXR and BA transporter expression. Moreover, NT stimulates the expression of FXR and BA transporters in Caco-2 cells; however, stimulated expression of BA transporters was attenuated in NT−/− enteroids. Therefore, we demonstrate that HFD disrupts the BA metabolism and ileal FXR and BA transporter axis which are improved in the absence of NT, suggesting that NT contributes to HFD-induced disruption of BA metabolism and plays an inhibitory role in the regulation of ileal FXR and BA transporter signaling under obese conditions. Conversely, NT positively regulates the expression of ileal FXR and BA transporters under non-obese conditions. Therefore, NT plays a dual role in obese and non-obese conditions, suggesting possible therapeutic strategies for obesity control.
KW - cancer
KW - gut hormones
KW - high-fat diet
KW - metabolism
KW - obesity
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UR - http://www.scopus.com/inward/citedby.url?scp=85103863052&partnerID=8YFLogxK
U2 - 10.1096/fj.202001692R
DO - 10.1096/fj.202001692R
M3 - Article
C2 - 33811694
AN - SCOPUS:85103863052
SN - 0892-6638
VL - 35
JO - FASEB Journal
JF - FASEB Journal
IS - 5
M1 - e21371
ER -